Gamma-hydroxybutyrate compositions containing carbohydrate, lipid or amino acid carriers

ABSTRACT

The present invention provides compositions comprising at least one GHB moiety bonded to at least one physiologically compatible carrier molecule. The compositions can enhance the uptake of the drug, deliver effective therapeutic doses in a time-delayed fashion, or can target specific organs.

BACKGROUND OF THE INVENTION

[0001] Gamma-hydroxybutyric acid or “gamma-hydroxybutyrate” (GHB) is anendogenous compound with hypnotic properties that is found in many humanbody tissues. GHB is present, for example, in the mammalian brain, thehuman nervous system and other tissues. The extraordinary range of thepharmacological effects of GHB or its salts has attracted scientificattention for more than three decades. For example, GHB has been foundto have tissue-protective effects in animals and man in many differentorgans including brain, liver, lung, heart, kidney, gut and pancreatic Bcells. In brain the highest GHB concentration is found in thehypothalamus and basal ganglia and GHB is postulated to function as aneurotransmitter (Snead and Morley, 1981). The neuropharmacologiceffects of GHB include increases in brain dopamine, depression ofglucose utilization but not oxygen consumption in the brain, andhypothermia. GHB is converted to succinate and then metabolized via theKrebs cycle. Clinical trials have shown that GHB increases delta sleepand improves the continuity of sleep (Ladinsky et al., 1983; Stock etal., 1973; Laborit, 1973; Lapierre et al., 1990; Yamada et al., 1967;Grove-White and Kelman, 1971; Scharf, 1985).

[0002] In healthy human volunteers, low doses (about 30 mg/kg) of GHBmonosodium salt (sodium oxybate) promote a normal sequence of NREM andREM sleep lasting about 2-3 hours. These low doses also can induce REMand slow wave sleep and, in contrast to the hypnotics in common use,without the development of tolerance to these sleep-inducing effects intime. In addition, GHB increases total sleep time and REM sleep, and itdecreases REM latency (Mamelak et al., 1973; Yamada et al., 1967; Bedardet al., 1989), reduces sleep apnea (Series et al., 1992; Scrima et al.,1987), and improves general anesthesia (Hasenbos and Gielen, 1985).

[0003] Studies by R. Broughton and M. Mamelak, Can. J. Neur. Sci., 7, 23(1980), L. Scrima et al., Sleep, 13, 479 (1990), and M. B. Scharf al.,Am. Fam. Phys. 143 (July 1988) have evaluated the effects of GHB in thetreatment of narcolepsy. The results of these studies confirm that GHBtreatment substantially reduces the signs and symptoms of narcolepsy(e.g., daytime sleepiness, cataplexy, sleep paralysis and hypnagogichallucinations).

[0004] GHB has several clinical applications other than the treatment ofsleep disorders. GHB has been reported to reduce alcohol craving, thenumber of daily drinks consumed, and the symptoms of alcohol withdrawalin patients (Gallimberti et al., 1989; Gallimberti et al., 1992; Gessaet al., 1992). GHB has been used to decrease the symptoms of opiatewithdrawal, including both heroin and methadone withdrawal (Gallimbertiet al., 1994; Gallimberti et al., 1993). It has analgesic effects thatmake it suitable as a pain reliever (U.S. Pat. No. 4,393,236).Intravenous administration of GHB has been reported to reduceintracranial pressure in patients (Strong, A. 1984). Also administrationof GHB was reported to increase growth hormone levels in patients (Gerraet al., 1994; Oyama et al., 1970). GHB is also an effective therapeuticagent for the treatment of chronic fatigue syndrome and fibromyalgia(Scharf, U.S. Pat. No. 5,990,162).

[0005] Unfortunately, the efficacy of GHB is limited by the high dosesrequired to produce a therapeutic effect and by its short duration ofaction. Thus, a need exists for GHB compositions that can enhance theuptake of the drug, deliver effective therapeutic doses in atime-delayed fashion, and target specific organs.

SUMMARY OF THE INVENTION

[0006] The present invention provides a compound of formula (I):

[0007] wherein Y is H or a hydroxyl-protecting group, X is the residueof a carbohydrate and n has a value of 1 to the number of availablehydroxyl groups in said carbohydrate, or a pharmaceutically acceptablesalt thereof.

[0008] Preferably, X is a saccharide, and Y is H, a (C₄-C₆) acetal,(C₁-C₅) acyl or (C₁-C₅) alkyl.

[0009] Preferred carbohydrates are water-soluble or water-dispersible.In yet another preferred embodiment of the invention, X is the residueof a monosaccharide, the residue of a disaccharide or the residue of apolysaccharide.

[0010] Examples of compounds of formula (I) include1,2,3,4,6-pentakis(4-hydroxy-butyroyl)hexanose;6-(4-hydroxy-butyroyl)hexanose and1,2,3,4,6-pentakis(4-acetoxybutyroyl)hexanose.

[0011] In a further preferred embodiment of the compound of formula (I),X is the residue of a chemically-modified cellulose. Usefulchemically-modified cellulose compositions include water-soluble orwater-dispersible celluloses such as hydroxypropyl-methylcellulose,hydroxypropylcellulose or hydroxyethylcellulose.

[0012] Further provided by the present invention is a compound offormula (II):

(R′O(CH₂)₃CO₂)_(m)(ROC(O)(CH₂)₃OC(O))_(q)—(X)—(Y)_(n)-(Z)_(n)-(CO₂(CH₂)₃CO₂R)_(p)(O₂C(CH₂)₃OR′)_(k)  (II)

[0013] wherein R′ is H or a hydroxyl protecting group, R′ is H,(C₁-C₄)alkyl or benzyl, X and Z are each residues of a hydroxygroup-containing amino acid or a bis(carboxy)amino acid, Y is a moietycovalently linking X and Z, n is 0-1, m and k are 0 to the number ofavailable OH groups in X and Z, q and p are 0 to the number of availableCO₂ groups on X and Z, with the proviso that m and q are not both zeroand p and k are not both zero, or a pharmaceutically acceptable saltthereof.

[0014] An embodiment of the compound of formula II is a compound offormula (III):

[0015] wherein R′ is H or a hydroxyl-protecting group, R is H, (C₁-C₄)alkyl or benzyl, X is a residue of a hydroxy group-containing aminoacids, Z is a residue of a hydroxy group-containing amino acid or abis(carboxy)amino acid, Y is a moiety covalently linking X and Z, n is0-1, in is 1 to the number of hydroxy groups on amino acid X, p is 1 tothe number of CO₂H groups on the amino acid X or Z, or apharmaceutically acceptable salt thereof.

[0016] Preferably, m, p, q and k are individually 0-5, more preferably0-3, and most preferably 0-2.

[0017] In one preferred embodiment of the compound of formula (III),m=p=1, n is O and X is glutamic acid, tyrosine, aspartic acid,threonine, or a serine. In another preferred embodiment of the compoundof formula (III), m=p=1, n is 1, and Y is C(O)CH₂CH₂C(O) orC(O)CH═CH(CO).

[0018] The present invention also provides a compound of formula (IV):

[0019] wherein L and L′ are individually H, (C₁-C₆)alkyl or a hydroxylprotecting group or an organic moiety comprising at least one fattyalcohol, ester or analog thereof. At least one of L and L′ is saidmoiety (the FA moiety). Preferably, the FA moiety is (A)(Y)(Z)_(n), andwherein A is (C₂-C₆)alkyl, Y is H, OH, N(R¹)(R²)(R³) or [—O(PO₃⁻)-L-N(R¹)(R²)(R³)] wherein R¹, R² and R³ are each (C₁-C₄)alkyl or R¹and R² together with N are a (C₅-C₇)heterocyclic ring, optionallysubstituted with 1 or 2 N(R³), S, non-peroxide O or a combinationthereof; n is 1-2 and Z is YR, wherein Y is O, S, NH, N(CH₃), NHC(O) orOC(O) and R is (C₈-C₂₂)alkyl, optionally substituted with 1-2 doublebonds.

[0020] Preferably, one of L or L′ is (A)(Y)(Z)_(n) and the other is H;n=1, YZ is (C₁₀-C₂₀)alkylC(O), R¹, R² and R³ are methyl and/or A ispropyl or ethyl. Preferably, when L′ is a 2-substituted lecithin moiety,i.e., the C²OC(O)R² moiety of lecithin is replaced by C²OC(O)(CH₂)₃OLand Y is hexadecanoyl; L is not H. Preferably n=1 and (A)(Y)(Z)_(n) is—CH[CH₂Y][CH₂Z], e.g., is derived by replacement of the 2′-acyloxylmoiety of lecithin with L-O(CH₂)₃C(O)—. When one of L or L′ is1,3-dihexdecanoylprop-2-yl, the other is not H.

[0021] Generally, L and L′ are derived from organic polyols, such asglycerol, ethylene glycol, propylene glycol, 2,2′-hydroxyethyl ether andthe like. The organic moieties L and L′ can also be simple fatty acidesters of C⁴—OH or fatty alcohol esters of CO₂H.

[0022] The present invention also provides compounds of formula (V):

[0023] wherein L is defined above, n is 2-6, preferably 2-5, mostpreferably 2-3, and L″ is (C₂-C₁₂) alkyl, preferably (C₃-C₁₀)alkyl, mostpreferably (C₃-C₆)alkyl, wherein the alkyl chain is optionallyinterrupted by about 1-3-O-moieties, i.e., is the residue of an alkylenepolyol, preferably a 1,ω-alkylene diol such as 1,3-propane diol, or apolyoxyalkylene glycol. Examples of compounds of formula (V) include1,2,3-tris(4-hydroxy-butyroyl)propane and1,3-bis(4-acetoxybutyroyl)propane.

[0024] The present invention also provides a pharmaceutical compositioncomprising an effective amount of the compound of formula (I), (II),(III) or (V), or mixtures thereof in combination with a pharmaceuticallyacceptable carrier. The pharmaceutical composition of the presentinvention may be adapted for parenteral, oral, topical or localadministration.

[0025] The present invention also provides a therapeutic methodcomprising administering to a mammal afflicted with a pathology orcondition ameliorated by GHB, an amount of a compound of formula I, II,III, IV and/or V effective to treat said pathology or condition.

[0026] As used herein, the term “effective amount” means that thecomposition can deliver an amount of GHB to a target cell, tissue ororgan effective to accomplish a therapeutic objective, i.e., to altercellular metabolism or energetics or to ameliorate at least one symptomof one of the pathologies discussed herein.

BRIEF DESCRIPTION OF THE FIGURES

[0027] The following drawings from part of the present specification andare included to further demonstrate certain aspects of the presentinvention. The invention may be better understood by reference to one ormore of these drawings in combination with the detailed description ofspecific embodiments presented herein.

[0028]FIG. 1A shows a compound comprising esters of GHB and a fullycharged hexopyranose.

[0029]FIG. 1B shows a GHB and a partially charged hexopyranose ester.

[0030]FIG. 2 shows a GHB-sucrose ester.

[0031]FIG. 3 shows GHB linked to representative amino acids.

[0032]FIG. 4 shows GHB linked to amino acid conjugates.

DETAILED DESCRIPTION OF THE INVENTION

[0033] A. Definitions

[0034] The term “amino acid” comprises the residues of the natural aminoacids (e.g. Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Hyl, Hyp, Ile,Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr, and Val) in D or L form, aswell as unnatural amino acids (e.g. phosphoserine, phosphothreonine,phosphotyrosine, hydroxyproline, gamma-carboxyglutamate; hippuric acid,octahydroindole-2-carboxylic acid, statine,1,2,3,4,-tetrahydroisoquinoline-3-carboxylic acid, penicillamine,ornithine, citruline, α-methyl-alanine, para-benzoylphenylalanine,phenylglycine, propargylglycine, sarcosine, and tert-butylglycine). Theterm also comprises natural and unnatural amino acids bearing aconventional amino protecting group (e.g. acetyl or benzyloxycarbonyl),as well as natural and unnatural amino acids protected at the carboxyterminus (e.g. as a (C₁-C₆)alkyl, phenyl or benzyl ester or amide; or asan α-methylbenzyl amide). Other suitable amino and carboxy protectinggroups are known to those skilled in the art (See for example, T. W.Greene, Protecting Groups In Organic Synthesis; Wiley: New York, 1981,and references cited therein). An amino acid can be linked to theremainder of a compound of formula I through the carboxy terminus, theamino terminus, or through any other convenient point of attachment,such as, for example, through the sulfur of cysteine.

[0035] The term “hydroxy amino acid” includes naturally occurring,synthetic and semi-synthetic amino acids, such as serine, threonine,tyrosine and hydroxyproline. Preferably the amino acids are a-aminoacids, most preferably with ω-hydroxyl groups.

[0036] The term “carbohydrate” as used herein is defined to includepolyhydroxy aldehydes, or polyhydroxy ketones or substances that yieldsuch compounds on hydrolysis. The term “carbohydrate” includesmonosaccharides, oligosaccharides, disaccharides, trisaccharides,tetrasaccharides, pentasaccharides, hexasaccharides, polysaccharides,homopolysaccharides, and heteropolysaccharides. The term includes any ofthe aldoses, as well as glucose, dextrose, mannose, galactose arabinose,xylose, ribose, fructose, sucrose, altrose, allose, idose, gulose,talose, lyxose, threose, erythrose, apiose, and any of the same in acidform. The term also includes deoxy sugars and deoxy-aldoses, includingrhamnose and fucose. The term further includes glyceraldehyde,cellulose, starch, glycogen, and amylose. The term also includescarbohydrate derivatives, such as acetals, ketals, acyl esters and thelike. Chemically modified polysaccharides such as sucralfate andmodified starches are also within the scope of the term. Additionalsuitable carbohydrates of the present invention may be found in Noller,C., Chemistry of Organic Compounds, 2nd ed. (W. B. Saunders Co., 1957).

[0037] The term “saccharide” includes monosaccharides, disaccharides,trisaccharides and polysaccharides. The term includes glucose, sucrose,fructose and ribose, as well as deoxy sugars such as deoxyribose and thelike. Saccharide derivatives can conveniently be prepared as describedin International Patent Applications Publication Numbers WO 96/34005 and97/03995.

[0038] The term “oligopeptide” describes a sequence of 2 to 25 aminoacids (e.g. as defined hereinabove) or peptidyl residues. The sequencemay be linear, branched or cyclic. For example, a cyclic peptide can beprepared or may result from the formation of disulfide bridges betweentwo cysteine residues in a sequence. An oligopeptide can be linked tothe remainder of a compound of formula I through the carboxy terminus,the amino terminus, or through any other convenient point of attachment,such as, for example, through the sulfur of a cysteine. Preferably apeptide comprises 3 to 25, or 5 to 21 amino acids. Peptide derivativescan be prepared as disclosed in U.S. Pat. Nos. 4,612,302; 4,853,371; and4,684,620.

[0039] The term “linking moiety” or “linker” as used herein refers to anat least divalent organic molecule that can join two amino acids oroligopeptidyl residues by reaction with functional groups therein. Suchmoieties include alkane and alkene dicarboxylic acids and diamines.

[0040] The term “alkyl” includes branched, straight-chain and cyclicalkyl groups, including (cycloalkyl)alkyl.

[0041] A fatty alcohol is a (C₈-C₂₂)alkanol, preferably a(C₁₀-C₂₀)alkanol, optionally comprising 1-3 double bonds; a fatty acidis a (C₈-C₂₂)alkanoic acid (i.e., (C₁-C₁₁)C(O)OH), optionally comprising1-3 double bonds.

[0042] The term “hydroxyl protecting group” includes removable hydroxymoiety protecting groups known to the art, such as acid- or base-labilegroups such as acetals (THP, (1-ethoxy)ethyl), tris(alkyl)silyl groups(Me₃, Si, (t-Bu(Me₂)Si)), (C₂-C₇)acyl groups (acetyl), as well as groupsthat can be removed by hydrogenolysis, such as benzyl. See, also, part(C)(a), hereinbelow, which references additional OH protecting groups.

[0043] B. Applications

[0044] GHB has been shown to be effective in treating narcolepsy andsleep disorders (Lee, 1977; Mamelak, 1977; Hoes, 1980; Scharf, 1985;Scrima, 1990; Gallimberti, 1992; Series, 1992; Lammers, 1993), reducingalcohol craving and alcohol withdrawal symptoms (Gallimberti et al.,1989; Gallimberti et al., 1992; Gessa et al., 1992), reducing opiatewithdrawal symptoms (Gallimberti et al., 1994; Gallimberti et al.,1993), reducing pain (U.S. Pat. No. 4,393,236), reducing intracranialpressure in patients (Strong, A., 1984), and increasing growth hormonelevels in patients (Gerra et al., 1994; Oyama et al., 1970). Thecompounds and compositions of the present invention can also be used inthe treatment of any of these disorders or conditions in patients.

[0045] GHB has been used with other analgesics, neuroleptics, or with asubliminal barbiturate dose for use as an anesthesia. GHB has been usedin closed cranio-cerebral trauma and as soporifics (U.S. Pat. No.5,380,937). Therefore, the compounds of the present invention can alsobe used in combination with analgesics, neuroleptics or barbiturates foruse as an anesthesia. The inventors contemplate the use of the GHBcompositions of the present invention as a narcotic, hypnotic, or as asoporific.

[0046] The present invention provides compounds and pharmaceuticalcompositions that can be used in the treatments of hypnosis; narcolepsy(particularly cataplexy); drug abuse; anxiety; cerebrovascular diseases;central nervous system disorders, neurological disorders, includingParkinson's Disease and Alzheimer Disease; Multiple Sclerosis; autism;depression; inflammatory disorders, including those of the bowel, suchas irritable bowel disorder, regional illitis, and ulcerative collitis;autoimmune inflammatory disorders; certain endocrine disturbances anddiabetes. The present compounds can also be administered for the purposeof tissue protection, including protection following hypoxia/anoxia suchas in stroke, organ transplantation, organ preservation, myocardialinfarction or ischemia/reperfusion injury; protection followingradiation, progeria, or an increased level of intracranial pressure,e.g., due to head trauma. The present compounds can be used to treatother pathologies believed to be caused or exacerbated by lipidperoxidation and/or free radicals, such as pathologies associated withoxidative stress, including normal aging.

[0047] C. Availability and Preparation of Compounds of the PresentInvention

[0048] GHB is available from the Aldrich Chemical Co., Milwaukee, Wis.,and can be employed to prepare the compounds within the scope of formula(I) or (II). The GHB compositions of the present invention can beprepared by and administered by any of the means described herein,particularly those described in the section and the examples, or by anymeans as would be known to those of skill in the art.

[0049] A compound of the present invention can be employed as the freeacid or alcohol, or as a pharmaceutically acceptable salt or esterthereof. Such salts can be formed from acids or amino groups describedherein, by methods available to one or ordinary skill in the art. Incases where compounds are sufficiently basic or acidic to form stablesalts with nontoxic organic acids or metal salts, administration of thecompounds as salts may be appropriate. Examples of pharmaceuticallyacceptable salts are organic acid addition salts formed with acids whichcan form a physiological acceptable anion, for example, tosylate,methanesulfonate, acetate, citrate, malonate, tartarate, succinate,benzoate, ascorbate, α-ketoglutarate, and α-glycerophosphate. Suitableinorganic salts may also be formed, including hydrochloride, sulfate,nitrate, bicarbonate, and carbonate salts. Pharmaceutically acceptablesalts may be obtained using standard procedures well known in the art,for example by reacting a sufficiently basic compound such as an aminewith a suitable acid affording a physiologically acceptable anion.Alkali metal (for example, sodium, potassium or lithium) or alkalineearth metal (for example calcium) salts of carboxylic acids can also bemade. The cations can also be readily exchanged with other metal ororganic cations, such as Ca⁺, K⁺, Li⁺, or (R)₄N⁺ wherein each R is H,phenyl, (C₁-C₆)alkyl or hydroxy(C₁-C₆)alkyl, i.e., ammonium orhydroxyethyl amine salts.

[0050] Hydroxy protecting groups such as esters, ethers, acetals andketals may be utilized in the present compounds. Useful hydroxyprotecting groups are descried in Greene, T. W.; Wutz, P. G. M.,“Protecting Groups in Organic Synthesis”, 2nd ed., John Wiley & Sons,Inc (1991).

[0051] a) Preparation of Carbohydrate-GHB Compounds

[0052] GHB can be esterified with (C₁-C₄)alkanols or the benzyl esterprepared. For ester preparation methods, see S. Ege, Organic Chemistry,p. 454-455, 459, 466-467 (D. C. Heath and Co., 1984). See also,Pouillart et al., Eur. J. Pharm. Sci., 7, 93-106 (1998). Then the OHgroup can be protected by formation of an acetal or by alkanoylation orbenzoylation with an alkanoyl or benzoyl chloride or with anhydrides.Other useful acid- and base-labile hydroxy-protecting groups aredescribed in Greene, T. W.; Wutz, P. G. M. “Protecting Groups In OrganicSynthesis” second edition, 1991, New York, John Wiley & Sons, Inc.

[0053] The ester can be removed and the acid can be activated ifnecessary, i.e., by formation of an acid chloride or anhydride. Forpreparation methods for 4-hydroxy-butanoic acid and its derivatives,see, Marvel et al., J. Am. Chem. Soc., 51, 260 (1929); Japanese patent63174947, German Pat. Nos. 237310, 237308 and 237309.

[0054] The activated carboxyl group of GHB can be reacted with thetarget hydroxyl groups in various sugars via ester bonds, as described,for example, in P. Pouillart et al., Eur. J. Pharm. Sci., 7, 93 (1998),P. R. Pouillart, Life Sciences, 63, 1739 (1998); P. Pouillart et al., J.Pharm. Sci., 81, 241 (1992), and references cited therein. Most types ofsugars, including triose (or glycerol) tetroses, pentoses and hexosescan be used to make the compounds of the present invention. In thelatter two cases, the open chain and ring (pyranoses and furanoses)forms may be used as scaffolds. An example of hexopyranose is depictedin FIG. 1a, where a maximum of 5 GHB molecules can be anchored to eachsugar monomer.

[0055] The therapeutic potential of these compounds is dependant on thestability of the compounds in various environments. It is contemplatedthat fully charged GHB compounds can be synthesized from sucrose(containing a furanose and a pyranose ring), glucose and one from anyopen chain hexose. These compounds may be synthesized by a single stepfrom free GHB or from its lactone.

[0056] In a fully charged molecule, i.e, (GHB)₅-Sugar, the hydrocarbonchains may provide adequate protection from enzymes present in thedigestive tract. These compositions may be susceptible to acid catalyzedhydrolysis, which depends on the steric environments around each esterbond. For example, the 6-OH ester bond will be readily hydrolyzed. Thesemolecules may be viewed as miniature micelles and can be transportedinto the circulatory system via the fat absorption mechanism.

[0057] Linking GHB to partially charged sugars may provide for betteruptake and delivery of the drug. As seen in FIG. 1b, the depictedcompound has only 3-GHBs attached to the sugar. The choice of hydroxylgroups for esterification can be based on the rates of hydrolysis of thecorresponding esters so that desired levels of free GHB can bemaintained within the cells of the target organ.

[0058] Free hydroxyl groups can be used to anchor various groups. Stericshielding of GHB-ester linkages enhances the stability of the compoundsin acidic medium. For example, one or more pairs of adjacent OH groupgroups on the sugar ring can be protected as acetals or as ketals, astaught by Pouillart et al., cited above, using acetals. The ketone canbe varied in bulk, in order to shield the ester linkages to a greater orlesser extent. The attachment of lipophilic groups, such as steroids orfatty acids, to GHB via e.g., ketal or acetal linkages, can enhance thetransfer across the blood-brain barrier. The use of a ketosteriod orbenzaldehyde to form a ketal or acetal is shown in FIG. 1(b). Alipophilic composition may also be useful for delivery of GHB via salvesor dermal patches. Free hydroxyl groups of the sugar may also be used toattach a second complementary therapeutic agent to the GHB composition.

[0059] b) Preparation of GHB Amino Acid Compounds

[0060] Amino acids (AA), serine, threonine, tyrosine, aspartic acid andglutamic acid contain side chains containing OH groups and/or secondCO₂H groups that can be coupled to GHB by ester linkages, followingN-protection (See FIG. 3). Each of these compounds could be linked totwo GHB molecules. Alternatively, the carboxylic acid of GHB can bereacted with an acid-protected amino acid to form the amide from theamine of the amino acid. Because the ester linkages of these compoundshave different steric environments, the hydrolysis rates of thesecompounds in vivo will vary. A significantly slow rate of hydrolysiswill be seen with serine and threonine, due to the ester linkagesassociated with their side chains. For tyrosine, the ester linkageassociated with the phenoxy side chain can be very rapidly hydrolyzed.Single amino acid compounds, i.e., AA-(GHB)₂ can only deliver 2 GHBmolecules, and due to the lack of steric shielding, these compounds mayhave limited stability in the stomach pH. However, tailored smallpeptides having 3 to 5 amino acids can significantly improve thequantity of GHB delivered and have enhanced stability.

[0061] It is contemplated that the compounds of the present inventionmay comprise two or more amino acids. Such compounds can be constructedby using covalent linking moieties such as succinic acid to couple theamino acids tyrosine and threonine, or using maleic acid to coupleaspartic and glutamic acids. Each of these conjugates comprises 4 GHBper molecule, where each ester linkage is in a significantly differentsteric shielding. (See FIG. 4). As backbones of the compounds, thesuccinic and maleic acid linkers have significantly different degrees offlexibility. Succinic acid has full rotational freedom, whereas usingmaleic acid, GHB molecules will be held in a cis orientation. Eachcompound, having two amide and four ester linkages, can give rise todistinct structural organizations with different stability and cellularuptake.

[0062] c) Preparation of Compounds of Formulas (IV) and (V)

[0063] Analogs of naturally occurring phospholipids and lipids are knownto the art. The compounds of formula II can be prepared as disclosed inPCT WO 92/03462; U.S. Pat. No. 5,223,263; PCT/US91/04289; orPCT/US94/05855. Lecithin or a sphingolipid can be partially hydrolyzedto yield one or more free OH groups and GHB attached as discussed above.

[0064] Compounds of formula (V) can be prepared by the reaction ofpolyols (L″(OH)_(n)) with 4-halobutyroylchloride, which is thenhydrolyzed and the 4-hydroxyl group protected, or the 4-halo group isdisplaced by L″O⁻ or an equivalent thereof

[0065] D. Administration

[0066] The invention provides a pharmaceutical formulation comprising acompound of formula (I), (II), or (III), together with one or morepharmaceutically acceptable carriers therefor and, optionally, othertherapeutic and/or prophylactic ingredients. The cations and carrier(s)must be “acceptable” in the sense of being compatible with the otheringredients of the formulation and not deleterious to the recipientthereof, i.e., they do not produce an adverse, allergic, or otheruntoward reaction when administered to an animal, or a human, atappropriate levels.

[0067] Pharmaceutical formulations include those suitable for oral orparenteral (including intramuscular, subcutaneous and intravenous)administration. Forms suitable for parenteral administration alsoinclude forms suitable for administration by inhalation or insufflationor for nasal, or topical (including buccal, rectal, vaginal, transdermalor sublingual) administration. The formulations may, where appropriate,be conveniently presented in discrete unit dosage forms, by bringing theactive compound into association with liquid carriers, solid matrices,semi-solid carriers, finely divided solid carriers or combinationsthereof, and then, if necessary, shaping the product into the desireddelivery system.

[0068] a) Parenteral Administration and Dosage Forms

[0069] The active compounds of the invention may be formulated forparenteral administration, e.g., formulated for injection viaintravenous, intraarterial, intramuscular, subcutaneous, intralesional,intraperitoneal or other parenteral routes. The preparation of anaqueous composition that contains a GHB agent as an active component oringredient will be known to those of skill in the art in light of thepresent disclosure.

[0070] The pharmaceutical dosage forms suitable for injection orinfusion can include sterile aqueous solutions or dispersions or sterilepowders comprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions. The compounds of the invention may be lyophilized formore ready formulation into a desired vehicle where appropriate. Forinjection or infusion, the active agent can optionally be encapsulatedin liposomes. In all cases, the ultimate dosage form should be sterile,fluid and stable under the conditions of manufacture and storage.

[0071] The liquid carrier or vehicle can be a solvent or liquiddispersion medium comprising, for example, water, ethanol, glycerol, apolyol (for example, glycerol, propylene glycol, liquid polyethyleneglycols, and the like), vegetable oils, nontoxic glyceryl esters, andsuitable mixtures thereof. The proper fluidity can be maintained, forexample, by the formation of liposomes, by the maintenance of therequired particle size in the case of dispersions, by the use ofsurfactants, or by the use of a substance, such as lecithin (e.g., acoating). Solutions of the active compounds as free acid orpharmacologically acceptable salts can be prepared in water suitablymixed with hydroxypropylcellulose and/or a pharmaceutically acceptablesurfactant. The prevention of the action of microorganisms can bebrought about by various antibacterial and antifungal agents, forexample, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, andthe like. In many cases, it will be preferable to include isotonicagents, for example, sugars, buffers or sodium chloride. Prolongedabsorption of the injectable compositions can be brought about by theuse in the compositions of agents delaying absorption, for example,aluminum monostearate and gelatin.

[0072] Sterile injectable solutions are prepared by incorporating theactive compounds in the required amount in the appropriate solvent withvarious of the other ingredients as required, followed by filteredsterilization. Generally, dispersions are prepared by incorporating thevarious sterilized active ingredients into a sterile vehicle whichcontains the basic dispersion medium and the required other ingredientsfrom those enumerated above. In the case of sterile powders for thepreparation of sterile injectable solutions, the preferred methods ofpreparation are vacuum-drying and freeze-drying techniques which yield apowder of the active ingredient plus any additional desired ingredientfrom a previously sterile-filtered, pyrogen-free solution thereof. Thepreparation of more, or highly, concentrated solutions for directinjection is contemplated, where the use of DMSO as solvent (althoughDMSO may not now be a permitted human drug) is envisioned to result inextremely rapid penetration, delivering high concentrations of theactive agents to a small area.

[0073] The compounds according to the invention may be presented in unitdose form in ampules, pre-filled syringes, small volume infusioncontainers, multi-dose containers with an added preservative, orindwelling pumps or dispensers, or in devices which allow for sustainedrelease of the compounds.

[0074] The active GHB agent may be included within a therapeuticcomposition to comprise about 0.1 to about 100 grams GHB per unit dosageform, and multiple doses can also be administered. As an example, onedosage could be dissolved in 1 ml of isotonic NaCl solution and eitheradded to 1000 ml of fluid or injected at the proposed site of infusion(see, for example, “Remington's Pharmaceutical Sciences” 15th Edition,pages 1035-1038 and 1570-1580). Some variation in dosage willnecessarily occur depending on the condition of the subject beingtreated. The person responsible for administration will, in any event,determine the appropriate dose for the individual subject.

[0075] b) Oral and Topical Administration and Dosage Forms

[0076] In addition to the compounds formulated for parenteraladministration, other pharmaceutically acceptable forms include, e.g.,tablets or other solids; liposomal formulations; time release capsules;and any other form currently used, including creams or lotions, whichthen may be admixed with an aqueous medium for oral administration.

[0077] Pharmaceutical formulations suitable for oral administration maybe presented as discrete unit dosage forms such as hard or soft gelatincapsules, cachets or tablets each containing a predetermined amount ofthe active ingredient; as a powder or as granules; as a solution, asuspension or as an emulsion; or in a chewable base such as a syntheticresin or chicle for ingestion of the active ingredient from a chewinggum. The active ingredient may also be presented as a bolus, syrup,electuary or paste. Tablets and capsules for oral administration maycontain conventional excipients such as binding agents, fillers,lubricants, disintegrants, or wetting agents. The tablets may be coatedaccording to methods well known in the art, i.e., with enteric coatings.

[0078] The tablets, troches, pills, capsules and the like may alsocontain the following: a binder, natural as gum tragacanth, acacia,cornstarch, or gelatin or synthetic as polyvinyl acetate; excipients,such as dicalcium phosphate; a disintegrating agent, such as cornstarch, potato starch, alginic acid and the like; a lubricant, such asmagnesium stearate; and a sweetening agent, such as sucrose, lactose,aspartame or saccharin may be added or a natural or synthetic flavoringagent.

[0079] When the dosage unit form is a capsule for admixing with aspecific volume of an aqueous medium, it may contain, in addition tomaterials of the above type, a liquid carrier, such as vegetable oil ora polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the dosage unit.For instance, tablets, pills, or capsules may be coated with gelatin,wax, shellac, sugar, natural or synthetic polymers, or both. A syrup orelixir may contain the active compounds, sucrose or fructose as asweetening agent, a preservative, a dye and/or a flavoring. Of course,any material used in preparing any unit dosage form should bepharmaceutically acceptable and substantially non-toxic in the amountsemployed.

[0080] Such compositions and preparations should contain at least 0.1%of the active compound. The percentage of the compositions andpreparations may, of course, be varied and may conveniently be betweenabout 2 to about 75% of the weight of the unit, or preferably between25-60%. The amount of active compounds in such therapeutically usefulcompositions is such that a suitable dosage will be obtained.

[0081] The GHB-containing agent may be packaged separately from or incombination with the excipients, salts, flavorings or any othercomponents described herein, to be admixed with an aqueous medium in thecase of oral or injectable formulations, or they may be incorporateddirectly with the food (i.e., a beverage, candy bar or cake) of thediet.

[0082] For topical administration, the present compounds may be appliedin pure form, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid. Examples of useful dermatologicalcompositions which can be used to deliver the compounds of formula I,II, or III to the skin are known to the art; for example, see Jacquet etal. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith etal. (U.S. Pat. No. 4,559,157) and Wortzman (U.S. Pat. No. 4,820,508).

[0083] Useful solid carriers for dermatological compositions includefinely divided solids such as talc, clay, microcrystalline cellulose,silica, alumina and the like. Useful liquid carriers include water,alcohols or glycols or water-alcohol/glycol blends, in which the presentcompounds can be dissolved or dispersed at effective levels, optionallywith the aid of non-toxic surfactants. Adjuvants such as fragrances andadditional antimicrobial agents can be added to optimize the propertiesfor a given use. The resultant liquid compositions can be applied fromabsorbent pads, used to impregnate bandages and other dressings, orsprayed onto the affected area using pump-type or aerosol sprayers.

[0084] Ointments, pastes, gels, lotions, soaps and creams may, forexample, be formulated with an aqueous or oily base with the addition ofsuitable thickening and/or gelling agents. Lotions may be formulatedwith an aqueous or oily base and will in general also contain one ormore emulsifying agents, stabilizing agents, dispersing agents,suspending agents, thickening agents, or coloring agents. Thickenerssuch as synthetic polymers, fatty acids, fatty acid salts and esters,fatty alcohols, modified celluloses or modified mineral materials can beemployed.

[0085] For systemic administration or as topical administration to theepidermis, compound(s) of formula (I), formula (II), or formula (III)may be formulated as the active ingredient of a transdermal patch.Suitable transdermal delivery systems are disclosed, for example, in A.Fisher et al. (U.S. Pat. No. 4,788,603), Chien et al. (U.S. Pat. No.5,145,682) or R. Bawa et al. (U.S. Pat. Nos. 4,931,279, 4,668,506 and4,713,224). The active ingredient can also be delivered viaiontophoresis, e.g., as disclosed in U.S. Pat. Nos. 4,140,122,4,383,529, or 4,051,842.

[0086] Formulations suitable for topical administration in the mouthinclude unit dosage forms such as lozenges comprising active ingredientin a flavored base, usually sucrose and acadia or tragacanth; pastillescomprising the active ingredient in an inert base such as gelatin andglycerin or sucrose and acacia; mucoadherent gels, and mouthwashescomprising the active ingredient in a suitable liquid carrier.

[0087] When desired, the above-described formulations can be adapted toprovide sustained release of the active ingredient employed, e.g., bycombination with certain hydrophilic polymer matrices, e.g., comprisingnatural gels, synthetic polymer gels or mixtures thereof.

[0088] Pharmaceutical formulations suitable for rectal administrationwherein the carrier is a solid are most preferably presented as unitdose suppositories. Suitable carriers include cocoa butter and othermaterials commonly used in the art, and the suppositories may beconveniently formed by admixture of the active compound with thesoftened or melted carrier(s) followed by chilling and shaping in molds.

[0089] Formulations suitable for vaginal administration may be presentedas pessaries, tampons, creams, gels, pastes, foams or sprays containing,in addition to the active ingredient, such carriers as are known in theart to be appropriate.

[0090] For administration by inhalation, the compounds according to theinvention are conveniently delivered form an insufflator, nebulizer or apressurized pack or other convenient means of delivering an aerosolspray. Pressurized packs may comprise a suitable propellant such asdichlorodifluoromethane, trichlorofluoromethane,dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In thecase of a pressurized aerosol, the dosage unit may be determined byproviding a valve to deliver a metered amount.

[0091] Alternatively, for administration by inhalation or insufflation,the compounds according to the invention may take the form of a drypowder composition, for example, a powder mix of the compound and asuitable powder base such as lactose or starch. The powder compositionmay be presented in unit dosage form in, for example, capsules orcartridges or, e.g., gelatin or blister packs from which the powder maybe administered with the aid of an inhalator or insufflator.

[0092] For intra-nasal administration, the compounds of the inventionmay be administered via a liquid spray, such as via a plastic bottleatomizer. Typical of these are the Mistometer® (Wintrop) and theMedihaler® (Riker). Nasal solutions are usually aqueous solutionsdesigned to be administered to the nasal passages in drops or sprays.Nasal solutions are prepared so that they are similar in many respectsto nasal secretions, so that normal ciliary action is maintained. Thus,the aqueous nasal solutions usually are isotonic and lightly buffered tomaintain a pH of 5.5 to 6.5, though other pH ranges disclosed herein thespecific example, such as pH 3 to about pH 9, or pH 6 to about 7.5, arecontemplated. In addition, preservatives, similar to those used inophthalmic preparations, and appropriate drug stabilizers, if required,may be included in the formulation. Various commercial nasalpreparations are known and include, for example, antibiotics andantihistamines and are used for asthma prophylaxis.

[0093] c) Dosages

[0094] A good safety profile for GHB consumption, when used long termfor treatment of narcolepsy, has been reported. Patients have beensafely treated for many years with GHB without development of tolerance(Scharf, 1985). Clinical laboratory tests carried out periodically onmany patients have not indicated organ or other toxicities (Lammers,1993; Scrima, 1990; Scharf, 1985; Mamelak, 1977; Mamelak; 1979;Gallimberti, 1989; Gallimberti, 1992; Gessa, 1992).

[0095] In the healthy volunteers study, the pharmacokinetics of threerising GHB doses (12.5, 25, and 50 mg/kg) were investigated. Thesefindings indicate that both the oral absorption and eliminationprocesses of GHB were capacity-limited though the degree of dosedependency was moderate (Palatini et al., 1993).

[0096] GHB has typically been administered in clinical trials as an oralsolution (Lee, 1977; Mamelak, 1977; Hoes, 1980; Scharf, 1985; Scrima,1990; Gallimberti, 1992; Series, 1992; Lammers, 1993). When used as anoral solution, the dosages have ranged from 20-45 milligrams perkilogram body weight, twice daily. (Mamelak, 1977.)

[0097] It will be appreciated that the amount of the compound of formula(I), (II), (III), (IV) or (V) required for use in treatment will varynot only with the particular compound selected but also with the routeof administration, the severity of the condition being treated and theage and condition of the patient and will be ultimately at thediscretion of the attendant physician or clinician.

[0098] Useful dosages of the compounds of formula (I), (II), (III), (IV)or (V) can be determined by comparing their in vitro activity, and invivo activity in animal models. Methods for the extrapolation ofeffective dosages in mice, and other animals, to humans are known to theart; for example, see U.S. Pat. No. 4,938,949.

[0099] Generally, the concentration of the compound(s) of formula (I),(II), (III), (IV) or (V) in a liquid composition, such as a lotion, willbe from about 0.01-25 wt-%, preferably from about 0.5-10 wt-%. Theconcentration in a semi-solid or solid composition such as a gel or apowder will be about 0.01-15 wt-%, preferably about 0.5-2.5 wt-%.

[0100] In general, however, a suitable dose will be in the range of fromabout 0.05 to 50 gm per day; or preferably from about 0.05 to about 500mg per kilogram body weight of the recipient per day, preferably in therange of 0.1 to 200 mg/kg/day.

[0101] The compound is conveniently administered in unit dosage form;for example, containing 0.1-20 g, conveniently 1-7.5 g, or moreconveniently, 2-5 g of active ingredient per unit dosage form.

[0102] The total daily dose, i.e., of about 0.05-50 g, may beadministered for about 1-4 months, or longer, as needed.

[0103] Ideally, the active ingredient should be administered to achievepeak plasma concentrations of the active compound of from about 0.5 toabout 75 μM, preferably, about 1 to 50 μM, most preferably, about 2 toabout 30 μM. This may be achieved, for example, by the intravenousinjection of a 0.05 to 5% solution of the active ingredient, optionallyin saline, or orally administered as a bolus containing about 1-100 mgof the active ingredient. Desirable blood levels may be maintained bycontinuous infusion to provide about 0.01-5.0 mg/kg/hr or byintermittent infusions containing about 0.4-15 mg/kg of the activeingredient(s).

[0104] The desired dose may conveniently be presented in a single doseor as divided doses administered at appropriate intervals, for example,as two, three, four or more sub-doses per day. The sub-dose itself maybe further divided, e.g., into a number of discrete loosely spacedadministrations; such as multiple inhalations from an insufflator or byapplication of a plurality of drops into the eye.

EXAMPLE 1 Preparation of 1,3-Bis(4-bromobutyroyl)propane (VII)

[0105]

[0106] A 500 ml round-bottomed flask was charged with 19.4 ml ofpyridine in 150 ml of dichloromethane (CH₂Cl₂), and stirring initiatedas the solution was cooled to 0° C. Propane-1,3-diol (8.0 g) was added,and stirring continued. A mixture of 26.4 ml of 4-bromobutyroyl chloridein 75 ml CH₂Cl₂ was added dropwise to the stirred pyridine/CH₂Cl₂ andstirring continued for 5 hrs at 0° C. The reaction mixture was washedwith 300 ml H₂O, the organic layer was isolated and washed with 100 mlin HCl aq, 100 ml NaCl aq and dried over MgSO₄ (anhydrous). The solventswere removed in vacuo to yield the product (VII) as a translucent lowviscosity oil.

EXAMPLE 2 Preparation of 1,3-Bis(4-acetoxybutyroyl)propane (VIII)

[0107]

[0108] A solution of 20.6 g potassium acetate and 3.49 g potassiumiodide in 306 ml acetic anhydride was stirred and the product (VII) ofEx. 1 added. The reaction mixture was refluxed with stirring for 12-16hrs, then cooled to 25° C. and diluted with 100 ml EtOAc. The reactionmixture was filtered, and the filtrate concentrated in vacuo. Ethylacetate (400 ml) was added and the resultant solution was washed with2×200 ml of 50% aq. NaHCl₃. The organic layer was isolated, dried (MgSO₄an.), filtered and concentrated in vacuo. Purification by flashchromatography yielded product (VIII) in 66.3% yield as a viscous lightyellow oil (93% pure).

REFERENCES

[0109] Bedard et al., Clin. Neuropharmacol., 12(1) 29 (1989)

[0110] Broughton and Mamelak, Can. J. Neur. Sci., 7, 23 (1980)

[0111] Gallimberti et al., Lancet, 2(8666), 787 (1989)

[0112] Gallimberti et al., Alcohol Clin. Exp. Res., 16(4) 673 (1992)

[0113] Gallimberti et al., Neuropsychopharmacology, 9(1) 77 (1993)

[0114] Gallimberti et al., Eur. Arch. Psychiatry Clin. Neurosci., 244(3)113 (1994)

[0115] Gerra et al., Int. Clin. Psychopharmacol., 9(3) 211 (1994)

[0116] Gessa et al., Clin. Neuropharmacol. 15 Suppl. 1 Pt. A 303A (1992)

[0117] Grove-White and Kelman, Br. J. Anaesth, 43(2) 110 (1971)

[0118] Hasenbos and Gielen, Anaesthesia, 40(10) 977 (1985)

[0119] Hoes et al., Encephale, 6(1) 93 (1980)

[0120] Laborit, Laboratoire d' Eutonologie. Hopital Boucicaut, Paris 15France, 1973

[0121] Ladinsky et al., Naunyn Schmiedebergs Arch Pharmacol., 322(1) 42(1983)

[0122] Lammers et al., Sleep 16(3) 216 (1993)

[0123] Lapierre et al., Sleep 13(1) 24 (1990)

[0124] Lee, Biochem Med. 17(3) 284 (1977)

[0125] Mamelak et al., Lancet, 2(7824) 328 (1973)

[0126] Mamelak et al., Biol. Psychiatry, 12(2) 273 (1977)

[0127] Mamelak et al., Biol. Psychiatry, 14(5) 821 (1979)

[0128] Oyama et al., Br. J. Anaesth., 42(12) 1105 (1970)

[0129] Palatini et al., Eur. J. Clin. Pharmacol., 45(4) 353 (1993)

[0130] Scharf et al., J. Clin. Psychiatry, 46(6) 222 (1985)

[0131] Scharf et al., Am. Fam. Phys., 143 (1988)

[0132] Scrima et al., Sleep, 13(6) 479 (1990)

[0133] Series et al., Am. Rev. Respir. Dis., 145(6) 1378 (1992)

[0134] Scharf et al., J. Clin Psychiatry, 46(6) 222 (1985)

[0135] Snead and Morley, Brain Res., 227(4) 579 (1981)

[0136] Stock et al., Naunyn Schmiedebergs Arch Pharmacol., 278(4) 347(1973)

[0137] Strong, Lancet, 1(8389) 1304 (1984)

[0138] Yamada et al., Electroencephalogr. Clin. Neurophysiol., 22(6) 558(1967)

[0139] All publications, patents, and patent documents are incorporatedby reference herein, as though individually incorporated by reference.The invention has been described with reference to various specific andpreferred embodiments and techniques. However, it should be understoodthat many variations and modifications may be made while remainingwithin the spirit and scope of the invention.

What is claimed is:
 1. A compound of the formula (I):

wherein Y is H or a hydroxyl-protecting group, X is the residue of acarbohydrate and n has a value of 1 to the number of available hydroxylgroups in said carbohydrate, or a pharmaceutically acceptable saltthereof.
 2. The compound of claim 1 wherein X is a saccharide.
 3. Thecompound of claim 1 wherein Y is H, a (C₄-C₆)acetal, (C₁-C₅)acyl or(C₁-C₅)alkyl.
 4. The compound of claim 1 wherein X is the residue of amonosaccharide or the residue of a disaccharide.
 5. The compound ofclaim 1 wherein X is the residue of a polysaccharide.
 6. The compound ofclaim 4 or 5 wherein the residue contains at least one CHOH—CHOH moietythat is protected as an acetal or ketal.
 7. The compound of claim 1wherein X is the residue of a chemically modified cellulose.
 8. Thecompound of claim 7 wherein the chemically modified cellulose ishydroxypropyl-methylcellulose, hydroxyethylcellulose orhydroxypropylcellulose.
 9. The compound of claim 1 wherein thecarbohydrate is a chemically modified saccharide or a chemicallymodified starch.
 10. A pharmaceutical composition comprising thecompound of claim 1 in combination with a pharmaceutically acceptablecarrier.
 11. The composition of claim 10 which is adapted for oraladministration.
 12. The composition of claim 10 which is adapted fortopical or local administration.
 13. A compound of the formula (II):(R′O(CH₂)₃CO₂)_(m)(ROC(O)(CH₂)₃OC(O))_(q)—(X)—(Y)_(n)-(Z)_(n)-(CO₂(CH₂)₃CO₂R)_(p)(O₂C(CH₂)₃OR′)_(k)  (II)wherein R′ is H or a hydroxyl-protecting group, R is H, (C₁-C₄)alkyl orbenzyl, X and Z are each residues of a hydroxy group-containing aminoacid or a bis(carboxy)amino acid, Y is a moiety covalently linking X andZ, n is 0-1, m and k are 0 to the number of available hydroxy groups onthe amino acids X and Z; q and p are 0 to the number of available CO₂groups on amino acids X and Z, with the proviso that both m and q andboth p and k are not zero, or a pharmaceutically acceptable saltthereof.
 14. A compound of the formula (III):

wherein R′ is H or a hydroxyl-protecting group, R is H, (C₁-C₄)alkyl orbenzyl, X is a residue of a hydroxy group-containing amino acids, Z isthe residue of a hydroxy group-containing amino acid or a bis(carboxy)group-containing amino acid, Y is a moiety covalently linking X and Z, nis 0-1, m is 1 to the number of available hydroxy groups in amino acidX, p is 1 to the number of available CO₂ groups on the amino acid X orZ, or a pharmaceutically acceptable salt thereof.
 15. The compound ofclaim 13 wherein each of m, q, p and k is
 1. 16. The compound of claim13 wherein m and k are 0, and q and p are
 1. 17. The compound of claim13 wherein n=0, m=0 and k=0 and X is glutamic acid, aspartic acid ortyrosine.
 18. The compound of claim 14 wherein m=p=1, n is 0 and X istyrosine, threonine, or serine.
 19. The compound of claim 14 whereinm=n=p=1 and Y is C(O)CH₂CH₂C(O) or C(O)CH═CH(CO).
 20. A compound offormula (IV):

wherein L and L′ are individually H, (C₁-C₆)alkyl or a hydroxylprotecting group or an organic moiety comprising at least one fattyalcohol, fatty ester or analog thereof, wherein at least one of L and L′is said moiety.
 21. The compound of claim 17 wherein at least one of L′or L is -(A)(Y)(Z)_(n), wherein A is (C₁-C₆)alkyl, Y is H, OHN(R¹)(R²)(R³) or [—O(PO₃ ⁻)-AN(R¹)(R²)(R³), wherein R¹, R² and R³ areeach (C₁-C₄)alkyl or R¹ and R² together with N are a (C₅-C₇)heterocyclicring, optionally substituted with 1 or 2 N(R³), S, non-peroxide O or acombination thereof; n is 1-2 and Z is YR, wherein Y is O, S, NH,N(CH₃), NHC(O) or OC(O) and R is (C₈-C₂₂)alkyl, optionally substitutedwith 1-2 double bonds, or a pharmaceutically acceptable salt thereof,with the proviso that when one of L or L′ is1,3-dihexadecanoylprop-2-yl, the other is not H.
 22. The compound ofclaim 21 wherein L′ is -(A)(Y)(Z)_(n) and L is H, (C₁-C₆)alkyl or ahydroxyl protecting group.
 23. The compound of claim 21 or 22 wherein Yis OC(O).
 24. The compound of claim 20 wherein R is (C₁₀-C₂₂)alkyl. 25.The compound of claim 21 or 22 wherein Y is —O(PO₃ ⁻)CH₂CH₂N(CH₃)₃ ⁺.26. The compound of claim 21 or 22 wherein (A)(Y)(Z)_(n) is—CH[CH₂Z][CH₂Y].
 27. A compound of the formula (V):

wherein L is individually H, (C₁-C₆)alkyl or a hydroxyl protectinggroup, n is 2-6, and L″ is (C₂-C₁₂)alkyl, optionally interrupted by1-3-O—.
 28. The compound of claim 27 wherein L″ is the alkyl residue of1,ω-alkylene diol.
 29. The compound of claim 27 wherein L″ is —(CH₂)₃—and n is
 2. 30. The compound of claim 27 wherein L is (C₂-C₇)acyl. 31.The compound of claim 27 where L is acetyl. 32.1,3-bis(4-acetoxybutyroyl)propane.
 33. The use of a compound of any ofclaims 1-32 in medical therapy.
 34. The use of a compound of any ofclaims 1-32 to prepare a medicament to treat a condition or pathologyamenable to treatment with gamma-hydroxybutyrate.
 35. A method fortreating a mammal afflicted with a condition or pathology amenable totreatment by gamma-hydroxybutyrate (GHB) comprising administering tosaid mammal an effective amount of a compound of any of claims 1-32. 36.A pharmaceutical composition comprising a compound of any of claims 1-32in combination with a pharmaceutically acceptable carrier.